1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride ("terazosin hydrochloride") is disclosed in U.S. Pat. No. 4,026,894. The compound is used for the treatment of hypertension and benign prostatic hyperplasia. Pharmaceutical compositions comprising terazosin and its salts are disclosed in U.S. Pat. No. 4,112,097.
Terazosin hydrochloride exists in several polymorphic forms including non-solvated crystalline forms: Form I-Form IV, a methanolate form, a monohydrate crystalline form and a dihydrate crystalline form. Form I is disclosed in U.S. Pat. No. 4,026,894. Form II is disclosed in U.S. Pat. No. 5,294,615. Form III and the methanolate form are disclosed in U.S. Pat. No. 5,412,095. Form IV is disclosed in U.S. Pat. No. 5,504,207 and was also disclosed in published Japanese Patent Application No. 5-078352 as type A-2. A monohydrate form was disclosed in U.S. Pat. No. 5,587,377. Terazosin.HCl dihydrate is disclosed in U.S. Pat. No. 4,251,532, and is marketed under the trade name Hytrin.COPYRGT..
U.S. Pat. No. 4,251,532 describes a process for the preparation of Terazosin.HCl dihydrate which involves as an initial step the preparation of terazosin anhydrous base using an acid scavenger. In a further step, the base form is converted to Terazosin.HCl dihydrate by the addition of hydrochloric acid.
U.S. Pat. No. 5,504,207 also relates to a process for the preparation of Terazosin.HCl dihydrate. The disclosed multi-step process involves an initial step in which terazosin Form IV is first prepared in the absence of an acid scavenger. The Form IV is then converted by a second reaction to Terazosin.HCl dihydrate.
Canadian Pat. No. 2,150,985 describes a process for preparing Terazosin.HCl dihydrate which initially involves the preparation of terazosin free base. The free base form is then reacted by suspension in water and the addition thereto of a molar equivalent of aqueous hydrochloric acid to produce Terazosin.HCl dihydrate.
The known methods discussed hereinabove are not as industrially efficient or as commercially optimized as possible. Generally speaking, the references require various forms of terazosin for their initial step and subsequent processes steps are required to separate these forms from the reaction by-products. Then, one must still perform more work to convert these terazosin forms to Terazosin.HCl dihydrate. It is well known in industrial economics that every processing step usually adds to the complexity and thereby the cost of a process. Additional cost factors include increasing preparation time and increasing the volumes and types of materials which must be kept on hand as starting materials and as waste products of the process. Moreover, any Terazosin.HCl dihydrate process which calls for the conversion of terazosin introduces a possibility of having other terazosin forms as impurities in the product which must then be separated out.